Charcot-Marie-Tooth (CMT) neuropathy, also called Hereditary Motor and Sensory Neuropathy (HMSN), is a clinically and genetically heterogeneous group of inherited peripheral neuropathies leading to progressive distal muscle weakness and sensory loss. CMT is frequently transmitted in an autosomal dominant manner. An estimated 1 in 2,500 persons has a form of CMT, making it a major diagnostic category within neurogenetic diseases (Skre, H., Clin. Genet. 6:98-118 (1974)). A current classification system divides CMT neuropathy into CMT type 1 (CMT1), which is characterized by demyelination and reduced nerve conduction velocities (NCVs)(typically <40 meters/sec), and CMT type 2 (CMT2), which denotes patients with axonal neuropathy, lack of myelin abnormalities in pathologic specimens, and nearly normal nerve conduction velocities (Dyck and Lambert, Arch. Neurol. 18:603-618 (1968)). Onset of symptoms associated with CMT typically occurs in adolescence or early adulthood; however, presentation may be delayed until mid-adulthood. The severity of symptoms is variable, even among members of the same family, with gradual progression of symptoms. Typical CMT symptoms include pes cavus, distal muscle weakness and atrophy, absent or diminished deep tendon reflexes, and mild sensory loss.
CMT1 has been divided into five subtypes (CMT1A-D, X), based on genetic linkage analysis; however, the CMT1 subtypes are clinically indistinguishable. CMT1A is associated with a 1.4 megabase (Mb) duplication on chromosome 17p11.2-p12 and a gene dosage effect for peripheral myelin protein (PMP22) (Matsumami et al., Nat. Gen. :176-179 (1992)). CMT1B is associated with mutations in the myelin protein zero gene (MPZ) (Hayasaka et al., Nat. Genet. 5:31-34 (1993). CMT1D is associated with mutations in the early growth response 2 element gene (EGR2) (Warner et al., Nat. Gen. 18:382-384 (1998) and CMTX is associated with mutations in the connexin 32 (Cx32) gene (Bergoffen et al., Science 262:2039-2042 (1993). Recently, mutations in the ganglioside-induced differentiation-associated protein 1 gene (GDAP1) have been associated with autosomal recessive demyelinating CMT as well as autosomal recessive axonal CMT with vocal cord paralysis (Nelis, E., et al., Neurology 59(12):1835-6 (2002). Patients that exhibit symptoms associated with CMT1, but that lack mutations in these known genes, have been assigned to subtype CMT1C.
Given the prevalence of CMT1 cases not linked to any known genetic loci, there is a need to identify genetic mutations associated with the CMT1 syndrome that can be used in a genetic screen to identify subjects susceptible to CMT1 neuropathy. The present inventors have discovered individuals with mutations in the small integral membrane protein of the lysosome/late endosome (“SIMPLE”) gene and have established a molecular linkage for CMT1C.